PD-L1 inhibitors are a group of drugs that inhibit the interaction between programmed death-ligand 1 (PD-L1) with its receptor, programmed cell death protein 1 (PD-1). This pathway, once activated, is a mechanism for tumor escape by T-cell exhaustion. Inhibition of this pathway is one approach to treating cancer. Nivolumab, a human IgG4 anti-PD-1 monoclonal antibody, works as an immune checkpoint inhibitor that blocks this pathway. Nivolumab is used as treatment of chemotherapy refractory advanced non-small cell lung cancer (NSCLC). As immunotherapy agents, such as nivolumab, become more widely used in treating NSCLC, medical practitioners face a challenge in the evaluation of the clinical efficiency of such immunotherapy agents.
There are no standard guidelines for evaluating response to treatment with PD-L1 checkpoint inhibitors such as nivolumab. In clinical practice, conventional radiological tools, including Response Evaluation Criteria in Solid Tumors (RECIST), have been employed. The RECIST criteria consider a significant increase in the size of tumor lesions and the development of new lesions to be unequivocal disease progression. Conventional approaches such as the RECIST criteria are used as operational thresholds that mandate the cessation of current therapy and the initiation of an alternate therapeutic regime. However, these conventional approaches that take into account the widest diameter of the tumor, have underestimated the benefit of therapy to patients because of the increase in tumor dimensions in patients who otherwise responded favorably to the treatment.
Such patients may be referred to as “pseudoprogressors”. Some patients respond to immunotherapy with tumor shrinkage or stable disease and are thus more likely to be accurately characterized by the RECIST criteria. However, pseudoprogressors may exhibit distinct immune-related patterns of response, including new lesions associated with edema, infiltrates of immune cells, and transient increases in baseline tumor lesions. Delayed clinical responses to immunotherapeutic agents may also be observed, resulting in an initial increase in total tumor burden which is then followed by tumor regression. These pseudoprogressor findings would be misclassified by conventional approaches as progressive disease, which may lead to poor patient outcomes because treatment that would be helpful is mischaracterized as ineffective. Additionally, positron emission tomography (PET) also shows false positives because of the activation of T-cells against cancer cells, which may lead to uptake of fluorodeoxyglucose (FDG). Thus, conventional approaches to predicting patient response to immunotherapy are not optimal.